Mukhtar in Pharmacology of the Skin describes the communication between cells as being mediated by different biomolecules, such as hormones. These so called primary messengers bind to specific receptors on the cell surface. The binding of the primary messenger of a primary messenger to its receptor conveys a certain information to the cell which is subsequently transduced through the membrane by a chain of signaling. This process involves various membrane structures and leads to the activation of an enzyme located at the intracellular side of the membrane. The stimulated enzyme generates a second messenger which evokes the cellular response; in most cases, by the activation of other enzymes. By these steps, the initial extracellular signal is converted into an intracellular signal. This process is called signal transduction.
The inositol cascade represents one of several signal transducing pathways. In its course, 2 second messengers, diacyglycerol (DG) and inositol triphosphate (IP3) are released. DG remains in the membrane and activates protein kinase C (PKC). IP3 acts by releasing calcium ions from their intercellular stores. The calcium ions subsequently evoke the cellular response, mainly by activating PKC.
Protein kinases regulate cellular responses by phosphorylation pathways of substrate proteins (eg. receptors or enzymes) and thereby alter their state of activity. In the case of the inositide cascade, PKC mainly performs this reaction. sphingosine dose-dependently inhibits PKC, but also binds to calmodulin (CaM) function and therefore inhibits CaM function Keratinocyte intercellular adhesion molecule (ICAM-1) is thought to be involved in dermal lymphocyte infiltration. The PKC activating phorbol ester, PMA has been reported to induce the expression of ICAM-1 in normal human keratinocytes. This effect can be blocked by a PKC inhibitor and suggests that PKC might play a role in ICAM-1 expression.
Tendons often pass through a protective sheath where they curve around bones or change directions. Excessive movement of the tendon can cause irritation, and if the friction continues, an over production of synovial fluid can cause tenosynovitis and a compression of the median nerve. Chronic distention of the tendon sheath can produce fibrosis in the carpal canal reducing the space for the flexor tendons, which will irritate the median nerve and produce a perineural fibrosis.
The repetitive hand motion initiates the pathology described above. Musicians, secretaries, athletes, short order cooks, computer programmers, sign language communicators, beauticians, and many workers in industry repeating the same act for extended periods of time.
Protein kinases regulate cellular responses by phosphorylation of substrate proteins (eg, receptors or enzymes) and thereby altering their state of activity. In the case of the inositide cascade, PKC mainly performs this reaction. sphingosine dose-dependently inhibits PKC, but also binds to calmodulin (CaM) function and therefore inhibits CaM function. The PKC activating phorbol ester, PMA has been reported to induce the expression of ICAM-1 in normal keratinocytes. This effect can be blocked by a PKC inhibitor and suggests that PKC might play a regulatory role in ICAM-1 expression.
Phytosphingosine inhibits PKC a and PKC b, as well as many other isoforms of PKC. This would mean that TGF beta would be inhibited so as to stop the excessive collagen production. In addition collagenase would be up regulated which would remodel the pathologically formed collagen. VEGF would be inhibited and this would prevent the synovial sheath from distending from fluid and which leads to tenosynovitis and a compression neuritis, as well as neovascularization of the sheath. TGF beta & PDGF would not be creating a thicker synovial sheath or forming adhesions between the tendon and the synovial sheath. In addition ICAM-1 would be inhibited as would LFA-1 greatly reducing the white blood cells migrating out of the synovial blood vessels. These white cells are greatly responsible for the inflammation and the proliferative changes in the synovial membrane as well as adhesions formed by scar.
TNF a is now recognized as being active in tenosynovitis and responsible for pain. This cytokine would be inhibited also.
At this point medical treatment consist of splints which are first used at night and then during the day if response is not evident. Steroid injections are used several times, rest from repetitive motions on the job and finally surgery when pain and weakness of the hand doesn't respond. Surgery does afford a quick fix, but additional fibrosis occurs and the patient will experience the previous symptoms.
What is needed is a topical Rx which when applied to the wrist will be delivered in an effective concentration so that it will inhibit the cytokines producing the inflammation which is responsible for the tenosynovitis and its compression of the median nerve. In addition TGF beta will be inhibited so that scar will not form. Inhibition of this growth factor up regulates collagenase and scar is remodeled so that the canal returns to its normal width and adhesions of the tendon, synovial membrane and median nerve are eliminated.
It must be emphasized that this syndrome begins with an inflammation of the synovial sheath of the tendon. If the invention were to be used in a preventative manner for workers at higher risk, it would prevent the development of the tenosynovitis. This initiates the syndrome and ultimately leads to the fibrosis in the carpal canal and possible neuropathy of the median nerve with permanent weakness.
A more focused attention in the work place must be made regarding tendon injury which results from repetitive strain injuries These injuries are caused and aggravated by repetitive movements sustained for long periods without adequate rest breaks. This behavior is known to cause tenosynovitis which may lead to Carpal tunnel syndrome. Prevention would be the most enlightened method, but the invention can be used prophylatically also when repetitive strain is not possible to eliminate. Certainly once clinically symptoms are evident, the Rx would be used twice daily for several weeks after symptoms ceased. Carpal tunnel syndrome is the most common hand disorder in Workman's Compensation claims. and its frequency could be dramatically reduced.
What is important to emphasize is that the fibrosis within the canal is stimulated by the tenosynovitis of distended the flexor tendons in the Carpal canal. If this inflammation is inhibited, the disease can not proceed to the formation of scar and the serious consequences of compression neuropathy.